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EWS-FLI1 fusion protein up-regulates critical genes in neural crest development and is responsible for the observed phenotype of Ewing's family of tumors.

Abstract
Tumor-specific translocations are common in tumors of mesenchymal origin. Whether the translocation determines the phenotype, or vice versa, is debatable. Ewing's family tumors (EFT) are consistently associated with an EWS-FLI1 translocation and a primitive neural phenotype. Histogenesis and classification are therefore uncertain. To test whether EWS-FLI1 fusion gene expression is responsible for the primitive neuroectodermal phenotype of EFT, we established a tetracycline-inducible EWS-FLI1 expression system in a rhabdomyosarcoma cell line RD. Cell morphology changed after EWS-FLI1 expression, resembling cultured EFT cells. Xenografts showed typical EFT features, distinct from tumors formed by parental RD. Neuron-specific microtubule gene MAPT, parasympathetic marker cholecystokinin, and epithelial marker keratin 18 were up-regulated. Conversely, myogenesis was diminished. Comparison of the up-regulated genes in RD-EF with the Ewing's signature genes identified important EWS-FLI1 downstream genes, many involved in neural crest differentiation. These results were validated by real-time reverse transcription-PCR analysis and RNA interference technology using small interfering RNA against EWS-FLI1 breakpoint. The present study shows that the neural phenotype of Ewing's tumors is attributable to the EWS-FLI1 expression and the resultant phenotype resembles developing neural crest. Such tumors have a limited neural phenotype regardless of tissue of origin. These findings challenge traditional views of histogenesis and tumor origin.
AuthorsSiwen Hu-Lieskovan, Jingsong Zhang, Lingtao Wu, Hiroyuki Shimada, Deborah E Schofield, Timothy J Triche
JournalCancer research (Cancer Res) Vol. 65 Issue 11 Pg. 4633-44 (Jun 01 2005) ISSN: 0008-5472 [Print] United States
PMID15930281 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • EWS-FLI fusion protein
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Protein c-fli-1
  • RNA-Binding Protein EWS
  • Transcription Factors
Topics
  • Animals
  • Cell Differentiation (genetics)
  • Cell Line, Tumor
  • Gene Expression Regulation, Developmental (genetics)
  • Gene Expression Regulation, Neoplastic (genetics)
  • Humans
  • Mice
  • Mice, SCID
  • Neoplasm Transplantation
  • Neural Crest (embryology, metabolism, physiology)
  • Oncogene Proteins, Fusion (genetics)
  • Proto-Oncogene Protein c-fli-1
  • RNA-Binding Protein EWS
  • Rhabdomyosarcoma, Embryonal (genetics, metabolism, pathology)
  • Sarcoma, Ewing (genetics, metabolism, pathology)
  • Transcription Factors (genetics)
  • Transfection
  • Transplantation, Heterologous
  • Up-Regulation

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